While nanotechnology has significant potential to address critical societal needs, innovators, policy makers and the public have concerns that the novel properties of engineered nanomaterials (ENMs) may cause harm. The number of new ENMs being generated is outpacing our efforts to understand the impacts of these materials. To advance our understanding and to keep pace with new innovations, we increasingly need advances in ENM synthesis, characterization, and bioactivity screening. Due to the complexity of this challenge, highly interactive multi-disciplinary teams are needed. We will collaborate with the Nanomaterials Health Implications Research (NHIR): Engineered Nanomaterials Resource and Coordination Core (ERCC). We expect that the NHIR will provide precision-engineered, multifunction ENMs to probe the roles of surface chemistry and core characteristics in function and properties. We propose that zebrafish offer unparalleled advantages to broadly interrogate the interactions between ENMs and biological systems. It is now widely accepted that data collected using the zebrafish model is readily translated to humans because of the genetic and molecular conservation between these species. More importantly, the unique inherent advantages of this model provides research opportunities not possible or feasible in other systems. For example, with a small quantity of test material, it is possible to determine whether a given ENM is able to interact with biological targets to produce molecular changes in the transcriptome, proteome and metabolome within the entire animal. Sensitivity of these `omic approaches? is very high and uncertainty is reduced since all cell types are assessed simultaneously in the whole zebrafish. Additionally, changes in growth, organ development, cardiovascular function, and complex neurobehavior are easily assessed at a high throughput. Over the past several years, we have developed a number of novel tools and assays to assess the impacts of ENMs on adult zebrafish and the microbiome to further increase the sensitivity of our multi-dimensional screens. In this proposal we will rapidly evaluate the bioimpacts of the provided materials using multi-dimensional, high throughput early life stage and adult zebrafish bioassays that we have pioneered. We will rapidly provide these comprehensive response profiles to the NHIR consortium. We will complete the following specific aims: 1) Define a comprehensive biological response profile produced by exposure to ENM using early life stage zebrafish; 2) Determine the long lasting impacts of early life stage exposure to ENMs; 3) Evaluate the impact of ingestion of ENMs on the microbiota in adult zebrafish; 4) Integrate ENM responses from the zebrafish and other biological systems to develop principles to reduce hazards. We expect that with completion of these proposed studies and through interactions and collaborations with the NHIR consortium, the expanded knowledge base of ENM-biological interactions will begin to reduce the uncertainty around ENM health risks. In so doing, we will progress toward the longer term goal to maximize the benefits and minimize the negative impacts of ENMs.